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2006 Grant - Robakis

Involvement of the Presenilin 1/PI3K/GSK-3 Signaling in Neuronal Apoptosis and Beta-Amyloid

Nikolaos K. Robakis, Ph.D.Mount Sinai School of MedicineNew York, New York

2006 Investigator-Initiated Research Grant

In Alzheimer's disease, the presenilin 1 protein plays a critical role in the production of the toxic beta-amyloid protein fragment. The normal function of the presenilin 1 is not well understood. It is found in the cells of many tissues throughout the body and is believed to be important for cell survival and development.

Nikolaos Robakis, Ph.D., and colleagues have found that some types of cells growing in culture require presenilin 1 to survive after they have grown to a high density. Without presenilin 1, the cells develop normally until they reach a high density, and then they undergo a pattern of cell death called apoptosis.

By studying these cells further, the researchers have found that presenilin 1 mediates its actions through a cell-signaling pathway, or chain of molecular events, known as the cadherin/phosphatidylinositol-3-kinase (PI3/Akt) pathway. Activation of this pathway by presenilin reduces the activity of another enzyme, called GSK-3. GSK-3 may be involved in promoting the formation of beta-amyloid and neurofibrillary tangles, another characteristic feature of Alzheimer pathology.

Dr. Robakis and colleagues have also found evidence that presenilin 1 is involved in other pathways that control the formation of beta-amyloid. They plan to continue their studies to understand how presenilin 1 functions in healthy cells and how mutations in the gene for presenilin 1 are associated with alterations in cell function that lead to some of the most characteristic features of Alzheimer's disease.